It is important to understand the basics of vascular smooth muscle cell physiology and the role of D1 receptor agonism in severe hypertension. In arteries, the tunica media is composed of smooth muscle cells activated by various neurotransmitters, hormones, and mechanical perturbations. Examples of endogenous stimuli responsible for inducing arterial smooth muscle contraction include norepinephrine, angiotensin II, endothelin, and thromboxane-A2. Passive stretching also induces arterial smooth muscle contraction and can be of importance when describing the autoregulation of blood pressure. When an endogenous stimulus acts on a vascular smooth muscle cell, calcium (Ca++) is released from the sarcoplasmic reticulum or from an influx across the cell membrane and binds to cytoplasmic calmodulin. The Ca++/calmodulin complex subsequently activates myosin light chain kinase (MLCK). MLCK phosphorylates myosin heads in the presence of adenosine triphosphate (ATP) thus enabling actin-myosin cross-bridge formation and smooth muscle contraction.[2][3]

Relaxation of smooth muscle occurs when there is decreased phosphorylation of myosin. There are three documented mechanisms by which this can occur: reduced entry or decreased release of Ca++ from the sarcoplasmic reticulum, inhibition of MLCK by increased cyclic guanosine monophosphate (cGMP), or dephosphorylation of MLCK by myosin phosphatase.[4]

Removal of Ca++ ions from the cytoplasm is achieved by two mechanisms. The primary mechanism is a plasma membrane-bound sodium (Na+)/Ca++ antiporter that effluxes one Ca++ ion and influxes three Na+ ions by utilizing the electrochemical gradient created by the Na+/potassium (K+) ATPase. The second mechanism by which Ca++ is removed from the cytoplasm is by a Ca++/ATPase located on the sarcoplasmic reticulum.

The contraction and relaxation of vascular smooth muscle is the mechanism by which changes in systemic vascular resistance (SVR) occur. Contraction of vascular smooth muscle causes a decrease in the cross-sectional area of the arterial lumen thus increasing SVR and afterload on the heart. Interpreting how changes in SVR affect blood pressure involve understanding the physiologic relationship between mean arterial pressure (MAP), cardiac output (CO), and SVR. MAP is equivalent to CO multiplied by SVR. Simply stated, this means that CO and SVR are directly correlated with MAP such that increases in SVR cause a rise in MAP. This physiologic perturbation manifests clinically as high blood pressure. In contrast, by decreasing SVR, MAP decreases.

Dopamine D1 receptors are located in the tunica media of arteries and exert their effects through a G-alpha stimulatory second messenger system. Upon ligand binding to D1-receptors, the alpha subunit dissociates from the intracellular domain of the transmembrane receptor and activates adenylate cyclase (AC). AC subsequently converts ATP to cyclic adenosine monophosphate (cAMP). All downstream effects are mediated by cAMP, the major second messenger in this pathway.[5]

Inside the cell, cAMP activates protein kinase A (PKA). PKA phosphorylates MLCK thus causing its inactivation. Since myosin cannot be phosphorylated by MLCK, the cross-bridge formation between myosin and actin does not occur, rendering the arterial smooth muscle cell unable to contract. The end result is the dilation of arteries producing decreased SVR, increased renal blood flow, natriuresis, and diuresis. These pharmacologic effects result in a decrease in blood pressure.[6]

Initiate treatment at 0.01 to 0.3 mcg/kg/minute then increase by 0.05 to 0.1 mcg/kg/minute every 15 minutes until desired blood pressure is reached or a max of 1.6 mcg/kg/minute is reached.

Renal impairment dosing: No adjustments

Hepatic impairment dosing: No adjustments

Pediatric Dosing

Severe Hypertension

Initiate treatment at 0.2 mcg/kg/minute then increases by 0.3 to 0.5 mcg/kg/minute every 20 to 30 minutes until target blood pressure is reached or until a max of 0.8 mcg/kg/minute is reached.[7]

Pediatric renal impairment dosing: No adjustments

Pediatric hepatic impairment dosing: No adjustments

Neonatal Dosing (Full-term or at least 2 kg)

Severe Hypertension

Initiate treatment at 0.2 mcg/kg/minute then increases by 0.3 to 0.5 mcg/kg/minute every 20 to 30 minutes until target blood pressure is reached or until a max of 0.8 mcg/kg/minute is reached.

Pharmacokinetics

The onset of action is 10 minutes in adults and 5 minutes in children. The half-life of fenoldopam is 5 minutes in adults and 3 to 5 minutes in children. It is metabolized by the liver and excreted primarily in the urine. The volume of distribution is 0.6 L/kg, and the duration is 1 hour.[8]

Contraindications

In pediatric patients, tachycardia may occur and may last up to 4 hours at doses greater than 0.8 mcg/kg/minute.

Monitoring

Routine vitals such as blood pressure and heart rate in addition to serial electrocardiograms (ECGs), renal/hepatic function tests, and serum potassium should be monitored during fenoldopam infusion.

Enhancing Healthcare Team Outcomes

A hypertensive crisis must be treated expeditiously and with the appropriate medications. Managing a hypertensive emergency requires a team-based approach starting in the emergency department or the intensive care unit, which includes the active participation of nurses and physicians from many specialties. During a hypertensive crisis, the healthcare team must coordinate patient care which includes:

Besides the physicians, the nurse and pharmacist must be fully aware of the drug's adverse reactions and monitor the patient. The pharmacist should be fully aware that the drug is not administered to patients with glaucoma and asthma or be used in combination with a beta-blocker for fear of inducing severe hypotension.

Once the patient has been stabilized, other healthcare personnel outside the emergency department will be involved in the patient's care. The type of providers involved in outpatient care differs based on etiology. However, a family practitioner or internist will always be responsible for initiating continuation of the patient's care.[10]

Evidence-Based Outcomes

Fenoldopam has been shown to have a renal protective effect in hypertensive patients with chronic kidney disease. However, a meta-analysis of many studies reveals that the drug can lower blood pressure effectively and decrease acute kidney injury, but in the long run, fenoldopam has no impact on renal replacement or the 30-day, in-patient mortality.[11][12] (Level II)